Jones Martin, Rose Ann
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Anemia. 2012;2012:323721. doi: 10.1155/2012/323721. Epub 2012 May 30.
C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ. Here we review the current understanding of the unique role of DOG-1 in maintaining stability of G-rich DNA in C. elegans and explore the question of why DOG-1 animals are crosslink sensitive. We propose a dynamic model in which noncovalently linked G-rich structures form and un-form in the presence of DOG-1. When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity. In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates. This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.
秀丽隐杆线虫为研究范可尼贫血（FA）提供了一个出色的模型系统，其特征之一是对链间交联剂敏感。对FA的理解核心在于对DOG-1的研究，DOG-1是解旋酶FANCJ的功能同源物。在此，我们回顾了目前对DOG-1在维持秀丽隐杆线虫富含G的DNA稳定性中独特作用的理解，并探讨了为什么缺失DOG-1的动物对交联敏感这一问题。我们提出了一个动态模型，即在有DOG-1存在的情况下，非共价连接的富含G的结构形成并解体。当没有DOG-1但存在交联剂时，富含G的结构很容易发生共价交联，导致交联形成增加，从而使交联敏感性增加。按照这种解释，DOG-1在FA途径中既不处于上游也不处于下游，而是与该途径协同作用以限制交联底物的可用性。该模型调和了在没有DOG-1功能时观察到的交联敏感性与其在维持富含G的DNA中的独特作用，并将有助于制定实验来检验这一假设。
